Arrhythmias that arise as a result of myocardial ischemia produce significant morbidity and mortality in the U.S. Available antiarrhythmic drugs are only marginally efficacious and most have frequent and significant toxicities. An understanding of the mechanisms of action of the antiarrhythmic drugs would enable the design of more clinically suitable pharmacologic agents. Studies have been done in this field in in situ heart, in vitro tissue and in single cardiac myocytes. To evaluate the molecular physiology of these drugs a common mode of action should be sought. Local anesthetic antiarrhythmic drugs slow conduction and depress automaticity partially by decreasing the Na current. To understand the molecular events that lead to this decrease in Na conductance it is necessary to measure the Na current under voltage clamp conditions when ionic activity gradients are known. Macroscopic current measurements from conventional clamp techniques do not permit a direct study of the molecular events associated with channel gating and block. This proposed study will study microscopic currents using the extracellular patch clamp technique to investigate the mechanism of blockade of Na channels in myocardial cells and in phospholipid bilayers made on patch clamp pipettes. With the patch clamp technique the direct study of the conductance states of individual ionic channels can be done and gating kinetics can be measured by the transition rates between the states. Excised membrane patches can also be used. The ionic compositions of the solutions bathing each side of the membrane is under experimental control and can be very rapidly changed. Disease states, e.g. myocardial ischemia, causes changes in intra- and extracellular H+, K+, Ca++ activity and these changes can be simulated. The contribution of the possible effects of changes in these ionic species in cardiac myocytes with and without application of antiarrhythmic drugs can be directly assessed.